Processes and intermediates for the preparations of prostaglandins

ABSTRACT

The present invention provides novel processes for the preparation of a cyclopentanone of Formula II and a lactone of Formula I, which are useful in the production of prostaglandins:  
                 
 
wherein Z, R 2 , R 3 , X 1 , X 2 , and   are as defined in the specification. 
The invention also provides novel enantiomerically enriched compounds.

FIELD OF THE INVENTION

The present invention relates to novel processes and intermediates forthe preparations of Prostaglandins and the derivatives thereof.

BACKGROUND OF THE INVENTION

Prostaglandins and the derivatives thereof have various biologicalactions, such as a vasodilating action, a prophlogistic action, aninhibitory action of blood platelet aggregation, a uterine musclecontraction action, an intestine contraction action and a loweringaction of intraocular pressure, and can be used in the preparation ofmedicaments for treatment or prevention of myocardial infarction, anginapectoris, arteriosclerosis, hypertension, or duodenal ulcer, which arevaluable for human as well as veterinary applications.

For the last few decades, many academic researchers and industrialorganizations have made tremendous efforts in exploring various keyintermediates as well as innovative processes for efficient andcost-saving synthesis of Prostaglandins (Collines, P. W. et. al., 1993,Chem. Rev. 93, 1533).

Specifically, lactones of Formula I are very important late-stageintermediates for synthesis of Prostaglandin 2α compounds.

-   -   I-1:        being a double bond, X₁and X₂ being protecting group    -   I-2:        being double bond, X₁ and X₂ being H    -   I-3:        being single bond, X₁ and X₂ being protecting group or H

For example, Lactones of Formula I-1 or I-2, wherein R₂ is methylene andR₃ is n-butyl, are key intermediates for the synthesis of natureProstaglandin F_(2α), E₂ and I₂, as reported in E. J. Corey, et al, J.Am. Chem. Soc. 1970, 92, 397; and J. Am. Chem. Soc. 1977, 99, 2006.

Lactones of Formula I-1 or I-2, wherein R₂ is methylene and R₃ isbenzyl, are advanced intermediates for the synthesis of Bimatoprost, asdisclosed in USP 2005/0209337.

Lactones of Formula I-1 or I-2, wherein R₂ is —CH₂O— and R₃ is asubstituted phenyl, are intermediates for the synthesis of(+)-Cloprostenol, Travoprost and (+)-Fluprostenol, as disclosed in EP0362686 and USP 2005/0209337.

Lactones of Formula I-3, wherein R₂ is methylene and R₃ is benzyl, areintermediates for the synthesis of Latanoprost, as disclosed in U.S.Pat. No. 5,359,095.

In industry, the above mentioned Lactones of Formula I have beenprepared from a famous intermediate III (the so-called Corey aldehyde)via the route depicted below in Scheme 1:

wherein P is a protecting group; and R₂ and R₃ are as defined above.

The synthesis of Corey aldehyde III (Corey's process) consists of morethan 12 reaction steps in a linear route with the use of cyclopentadieneas the starting material. In Corey's process, not only is it difficultto proceed with the production reproducibly but the final targetcompound is usually obtained in a low yield. In addition, the majordrawback of the Corey's process is associated with the poor selectivitytoward the reduction of the 15-ketone functional group on the ω-sidechain (Scheme 1), which often results in a considerable amount of the15-β isomer generated as a major impurity. [See Corey, et. al., 1987, J.Am. Chem. Soc., 109, 7925; Corey, et. al.,1972, J. Am. Chem. Soc., 94,8616; Corey, et. al., 1971, J. Am. Chem. Soc., 93, 1491; and Noyori, et.al., 1979, J. Am. Chem. Soc., 101, 5843). In order to remove the 15-βisomer, it is necessary to utilize chromatography in the Corey's processfor the separation of the isomers having slight differences in the R_(f)values.

Given the above, conventional approaches for producing Lactones ofFormula I encountered problems to be solved. The objective of theinvention is to provide a simpler as well as a cost-effective synthesisroute for Lactones of Formula I to eliminate the problems associatedwith the conventional processes, either in the aspect of a number ofsynthetic steps or in the necessity of removing unwanted isomers.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel processes for thepreparation of the key intermediates of Formula I, which are useful inthe production of prostaglandins:

wherein R₂ is a single bond or a C₁₋₄-alkylene or a group of formula—CH₂O—; R₃ is a C₁₋₇-alkyl or an aryl or an aralkyl, each of which isunsubstituted or substituted by a C₁₋₄alkyl, a halogen and atrihalomethyl; X₁ and X₂ are protecting groups for the hydroxy group orH, and

is a single or double bond.

In another aspect, the invention provides novel enantiomericallyenriched Cyclopentanones of Formula II,

wherein Z is an arbitrary group that does not participate in a couplingand deprotection reactions but acts as a leaving group in areduction/lactonization reaction; R₂, R₃, X₁, X₂ and

are defined as above, and processes for preparing the same.

In yet another aspect, the invention provides a novel enantiomericallyenriched lactone and novel enantiomerically enriched compounds usefulfor the production of the compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Definition

The term “alkyl” used herein refers to a straight or branchedhydrocarbon group containing 1 to 30 carbon atoms, such as methyl,ethyl, isopropyl, tert-butyl, and the like; or a cyclic saturatedhydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl,cyclopentyl, cyclohexyl, menthyl, and the like.

The term “lower alkyl” used herein refers to an alkyl containing 1 to 6carbon atoms such as methyl, ethyl, propyl, and the like.

The term “alkenyl” used herein refers to a straight or branchedhydrocarbon group containing 3 to 20 carbon atoms and one or morecarbon-to-carbon double bonds, such as pentenyl, propenyl, and the like;or a cyclic unsaturated hydrocarbon group having 5 to 20 carbon atomsand one or more carbon-to-carbon double bonds, such as cyclopentenyl,cyclohexenyl, and the like.

The term “alkynyl” used herein refers to a straight or branchedhydrocarbon group containing 3 to 20 carbon atoms and one or morecarbon-to-carbon triple bonds such as pentynyl, propynyl, and the like;or a cyclic unsaturated hydrocarbon group having 6 to 20 carbon atomsand one or more carbon-to-carbon triple bonds.

The term “aryl” used herein refers to a monocyclic or polycyclicaromatic hydrocarbon radical, such as phenyl, naphthyl, anthryl,phenanthryl and the like. The aryl may optionally be substituted withone or more substituents, including but not limited to, a halogen, analkoxyl, a thioalkoxyl, an alkyl, and an aryl.

The term “aralkyl” used herein refers a straight or branched hydrocarboncontaining 1 to 20 carbon atoms and one or more aryl group as describedabove, such as benzyl, benzhydryl, fluorenylmethyl, and the like.

Each of the above mentioned alkyl, alkenyl, alkynyl, aryl, and aralkylmay optionally be substituted with one or more substituents selectedfrom the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy,thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl,arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl or aheterocyclic group selected from the group consisting of pyridinyl,thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl,piperazinyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, and thelike.

The term “protective group” has the meaning conventionally defined inorganic synthetic chemistry, i.e., a group capable of protecting afunctional group or moiety of a compound against the attacks of achemical reaction. Examples of the protective group include, but are notlimited to, methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl,bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl,1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substitutedbenzyl, and SiR_(a)R_(b)R_(c) wherein R_(a), R_(b) and R_(c) are eachindependently a C₁₋₄ alkyl, phenyl, benzyl, a substituted phenyl, or asubstituted benzyl.

In the depiction of the compounds given throughout this description, athickened taper line

indicates a substituent which is in the beta-orientation(above the planeof the molecule or page), a broken flare line

indicates a substituent which is in the alpha-orientation (below theplane of the molecule or page), and a wavy line

indicates a substituent which is either in the alpha- orbeta-orientation or in a combination of these orientations.

ASPECTS OF THE INVENTION

In the present invention, a novel approach for the synthesis of aLactone of Formula I is depicted in scheme 2. All reactants are used intheir enantiomerically enriched form, typically with an optical purityof higher than 90% e.e.

A. Preparation of Novel Cyclopentanones of Formula II-1

As shown in Step (a) of Scheme 2, a Cyclopentanone of Formula II-1wherein Z is an arbitrary group that does not participate in couplingand deprotection reactions but acts as a leaving group in areduction/lactonization reaction; R₂ is a single bond or a C₁₋₄-alkyleneor a group of formula —CH₂O—; R₃ is a C₁₋₇-alkyl or an aryl or anaralkyl group, each of which is unsubstituted or substituted by aC₁₋₄-alkyl, a halogen, or a trihalomethyl; and P₁ and P₂ are the same ordifferent protecting groups for the hydroxy group, are prepared by acoupling reaction, which is preferably performed at a temperatureranging from −100° C. to 40° C., of an enantiomerically enriched ω-sidechain unit of a cuprate of Formula V (wherein R₂, R₃, and P₂ are asdefined above; R₄ is a non-interfering group; and X is —CN, —SCN,—OSO₂CF₃, or —S-phenyl-) derived from a vinyl halide of Formula V-1, avinyl stannane of Formula V-2 or an alkyne of Formula V-3,

wherein Y is a halogen; R₆ is a lower alkyl; R₂, R₃, and P₂ are asdefined above, as described in Chen, et. al., 1978, J. Org. Chem., 43,3450, U.S. Pat. No. 4,233,231, U.S. Pat. No. 4,415,501 and U.S. Pat. No.6,294,679; with an optically active Cyclopentenone of Formula IV, thepreparation of which has been disclosed in the co-pending patentapplication filed on the even date and entitled “PROCESSES FOR THEPREPARATIONS OF OPTICALLY ACTIVE CYCLOPENTENONES AND CYCLOPENTENONESPREPARED THEREFROM.”

Subsequently, the reaction is quenched with a base, e.g., ammoniumhydroxide or the like, and subjected to a work-up procedure conducted ina conventional manner. The resultant crude product can be purified by aconventional method, such as column chromatography, or the unpurifiedproduct can be directly used in the next reaction.

According to the embodiments of the invention, the substituent Z in theabove-mentioned Formulae is —OR₁, —N(R₁)₂, or —SR₁, where R₁ at eachoccurrence is independently an alkyl, an alkenyl, an alkynyl, an aryl oran aralkyl group each of which is unsubstituted or substituted with oneor more substituents selected from the group consisting of halogen,alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino,arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl,alkylaminocarbonyl, and carbonyl or a heterocyclic group selected fromthe group consisting of pyridinyl, thiophenyl, furanyl, imidazolyl,morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl,pyrrolidinyl and pyrrolidinonyl, or when Z is —OR₁, R₁ is a protectinggroup for the carboxyl group. Preferably, Z is —OR₁.

B. Preparation of Lactones of Formula I

As shown in Step (d) of Scheme 2, a Cyclopentanone of Formula II-1 orII-2 is reduced/lactonized to form a Lactone of Formula I-1 or I-2 witha reducing agent of Formula Y:M₁M₂(R₅)_(n)H Ywherein M₁ is Li, K, or Na or absent; M₂ is Al or B; n is 2 or 3; and R₅is hydrogen, an alkyl or an alkoxyl, in a suitable solvent. According tothe present invention, the reducing agent is selected from sodiumbis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride,lithium tri-tert-butoxyaluminohydride, a lithium tri-alkyl borohydride,a potassium tri-alkyl borohydride or a sodium tri-alkyl borohydride or amixture thereof. Preferably, the reducing agent is lithiumtri-sec-butylborohydride, lithium tri-amylborohydride, sodiumtri-sec-butylborohydride, potassium tri-sec-butylborohydride, orpotassium tri-amylborohydride or a mixture thereof. Most preferably, thereducing agent is lithium tri-sec-butylborohydride. The non-limiting,suitable solvent used in the above reaction can be selected fromtetrahydrofuran, ether, toluene, hexane, or a mixture thereof. Thereaction is carried out at a temperature ranging from −120° C. to theroom temperature, preferably from −100° C. to −40° C. The reducing agentis used in an amount such that the substrates or the reactants arecompletely reacted as monitored by Thin Layer Chromatography (TLC). Uponcompletion of the reaction, the Lactone of Formula I-1 or I-2 can beisolated from the reaction mixture by a work-up procedure such asremoving the excessive reducing agent, extraction, dehydration,concentration, and the like. The product may be further purified bycolumn chromatography or by crystallization.C. Deprotection of Cyclopentanones of Formula II-1 or Lactones ofFormula I-1

As shown in Step (b) of Scheme 2, the Cyclopentanone of Formula II-2 andthe Lactone of Formula I-2 are prepared by deprotecting a Cyclopentanoneof Formula II-1 and a Lactone of Formula I-1, respectively. Theconditions for carrying out such deprotection reactions are obvious topersons skilled in the art. For example, the Cyclopentanones of FormulaII-1 wherein each of P₁ and P₂ is a triethylsilyl protecting group aredissolved in a suitable solvent, such as a solvent mixture of acetoneand water in a volumetric ratio of 5 to 1, treated with a deprotectingagent such as hydrogen chloride, p-toluenesulfonic acid, or pyridiump-toluenesulfonate, and stirred at room temperature for 10 minutes to 10hours to obtain the deprotected product of formula II-2.

The crude Cyclopentanone product of II-2 contains a small amount ofstereoisomers generated from the conjugate addition reaction (couplingreaction), which can be further removed by column chromatography elutedwith single solvent or a mixture of two or more of hexane, heptane,ethyl acetate, toluene, ether, and isopropyl alcohol.

Alternatively, the stereoisomers present in the crude product II-2 canbe removed by the crystallization of the crude product. Thecrystallization is preferably carried out in a suitable organic solventselected from ethyl ether, petroleum ether, isopropyl ethyl ether, butylmethyl ether, ethyl acetate, toluene, isopropyl ethyl ketone, methylisobutyl ketone, hexane, heptane, isopropyl alcohol, methanol, ethanol,or acetic acid, or a mixture thereof.

D. Protection of Cyclopentanones of Formula II-2 or Lactones of FormulaI-2

Both the protected Lactone I-1 or non-protected Lactone I-2, as shown inScheme 2, can be further subjected to a reduction reaction withdiisobutylaluminum hydride (DIBAL) as well as a Wittig reaction toobtain the final target Prostaglandin. However, it is preferable to usethe protected Lactone I-1 to avoid excessive consumption of DIBAL aswell as Wittig reagents for reacting with the hydroxyl groups.

As illustrated in Scheme 2, step (c) is performed to protect theCyclopentanone of Formula II-2 or Lactone of Formula I-2. Suitableprotective groups used are trialkylsilyl, tetrahydropyranyl (THP), andthe like. Suitable reaction conditions are obvious to persons skilled inthe art. For example, the Lactone of Formula I-2 that is dissolved in anappropriate solvent selected from tetrahydrofuran, ethyl acetate,toluene, or dimethylformamide, or a mixture thereof, can be reacted withmore than 2 mol. eq. of a base such as a triakylamine or imidazole aswell as about 2 mol. eq. of tert-butyldimethylsilyl chloride at atemperature ranging from about 0 to 80° C. Subsequently, a work-upprocedure, such as filtration, extraction, dehydration, andconcentration is employed to obtain a protected Lactone of Formula I-1.According to the present invention, a Lactone of the Formula I-1a havinga high purity in its crystalline form was unexpectedly and surprisinglyobtained:

E. Synthesis of 13,14-dihydrolactones of Formula I-3

Lactones of Formula I-3, as shown in Scheme 3 below, which are usefulfor the synthesis of 13,14-dihydro-Prostaglandin F₂alpha, especially forthe synthesis of Latanoprost, may be prepared via one of the routes asdescribed below and illustrated in Scheme 3:

-   -   (i) Conducting a coupling reaction of the ω-side chain unit of a        cuprate of Formula VI, which may be prepared according to the        method disclosed in U.S. Pat. No. 6,852,880, with a        Cyclopentenone of Formula IV to obtain a protected        Cyclopentanone of Formula II-3, which is further subjected to        deprotection and reduction/lactonization reaction to obtain an        unprotected Lactone of Formula I-3;    -   (ii) Reacting a Cyclopentenone of Formula IV with a cuprate of        Formula V to obtain a Cyclopentanone of Formula II, which is        further subjected to deprotection, hydrogenation, and        reduction/lactonization reactions as depicted in steps (e)        and (d) to obtain an unprotected Lactone of Formula I-3; or    -   (iii) Converting the Cyclopentanone of Formula II obtained        according to the route recited in Item (ii) to a protected        Lactone of Formula I, which is further deprotected and        hydrogenated or hydrogenated without being deprotected to obtain        an unprotected or a protected Lactone of Formula I-3.        wherein Z, R₄, R₅, M₁, M₂, n, P₁, P₂, X₁ and X₂ are as defined        above.

The hydrogenation reaction of step (e) in Scheme 3 is performed underhydrogen in the presence of a hydrogenation catalyst and a suitablebase/electrophile reagent in a suitable solvent. Suitable hydrogenationcatalyst contains a metal selected from the group consisting ofpalladium, platinum, rhodium, and nickel and a mixture thereof. Examplesof the catalyst include Pd—C, Pt—C, and Ni. Suitable solvent can beselected from tetrahydrofuran, ethyl acetate, ethanol, or toluene, or amixture thereof.

The Lactone of Formula I is then subjected to a semi-reductive reactionwith diisobutyl aluminium hydride (DIBAL) as illustrated in Step (e)followed by Wittig reaction to produce a Prostaglandin, particularlyPGE₂ and PGF₂α series. The details regarding DIBAL and Wittig reactionsare available from prior art documents, such as Lee et. al., 1978, J.Chem. Soc., Perkin trans I 1179; EP-A-0639563; Corey et. al., 1969, J.Am. Chem. Soc., 91, 5675; and J. Am. Chem. Soc., 1972, 94, 8616.

The present invention not only provides a simple and easy approach forthe synthesis of Prostaglandins but solves the problems regarding thegeneration of excessive 15β-isomer, which results in the difficulty inthe final purification as encountered in Corey's process. Moreimportantly, the Cyclopentanone of Formula II prepared according toScheme 3 can be further purified by crystallization or simple columnchromatography to eliminate the 15β-isomer completely. In summary, thepresent invention provides a shortcut for the synthesis ofProstaglandins free of 15β-isomer.

F. Novel Compounds of Formula II

The invention further provides novel enantiomerically enriched compoundsof Formula II

having an optical purity of more than 95% enantiomeric excess; wherein Zis OR₁, and R₁, X₁, X₂,

, R₂ and R₃ are as defined above; with the proviso that the compound isnot the one represented by any of formulae X-1, X-2, X-3, X-4 and X-5:

wherein R₇ is an arbitrary substituent; AA is hydrogen or an amino acidresidue; and X₁, X₂,

, R₂ and R₃ are as defined above.

According to one embodiment of the invention, X₁ and X₂ in Formula IIare both hydrogen atoms; and R₁ is an alkyl, an alkenyl, or an alkynyleach of which is unsubstituted or substituted with one or moresubstituents selected from the group consisting of halogen, thioalkoxyl,thioaryloxy, alkylamino, and cyano, or a heterocyclic group selectedfrom the group consisting of morpholinyl, oxazolinyl, piperidinyl,piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl; or R₁is an aryl which is unsubstituted or substituted with one or moresubstituents selected from the group consisting of halogen, alkyl, aryl,alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino,cyano, alkoxycarbonyl, arylcarbonyl, alkylaminocarbonyl,arylaminocarbonyl and carbonyl; or R₁ is an aralkyl, which isunsubstituted or substituted with one or more substituents selected fromthe group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy,thioalkoxyl, thioaryloxy, alkylamino, cyano, alkoxycarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl and carbonyl.According to the more preferred embodiments of the invention, R₁ isC₁-C₁₀ alkyl, benzyl, naphthyl, or phenyl, each of which isunsubstituted or substituted with one or more substituents selected fromthe group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy,thioalkoxyl, thioaryloxy, alkylamino, cyano, alkoxycarbonyl,alkylaminocarbonyl, and morpholinyl.

According to the most preferred embodiments of the present invention,the compound of Formula II is selected from the group consisting of:

-   Ethyl    (1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane    acetate;-   Benzyl    (1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane    acetate;-   2-Naphthyl    (1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane    acetate;-   (1′R, 2′S, 5′R)-Menthyl    (1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane    acetate;-   2-Cyanoethyl (1R,2R,3R)    3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane acetate;-   3-Ethoxycarbonylphenyl    (1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane    acetate;-   4-Morpholineethyl    (1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane    acetate;-   Benzyl    (1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentane    acetate;-   2-Naphthyl    (1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentane    acetate;-   (1′R,2′S,5 ′R)-Menthyl    (1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentane    acetate;-   Ethyl    (1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentane    acetate;-   Ethyl    (1R,2R,3R)-3-hydroxy-2-[(3R)-hydroxy-4-(3-trifluoromethyl)phenoxy-1-butenyl]-5-oxo-cyclopentane    acetate; and-   Ethyl    (1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3R)-hydroxy-pentanyl]-5-oxo-cyclopentane    acetate.    G. Novel Enantiomerically Enriched Compounds of Formulae V-2a and    V-2b

The invention further provides novel enantiomerically enriched compoundsof Formulae V-2a and V-2b:

wherein R₆ is a lower alkyl, and P₄ is trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, tetrahydrofuranyl, tetrahydropyranyl, or1-ethoxyethyl.

EXAMPLES Example 14-[3-(Trifluoromethyl)phenoxy]-(3R)-triethylsilyloxy-1-butyne

(3R)-4-[3-(Trifluoromethyl)phenoxy]-3-hydroxy-1-butyne (6.7 g, 29 mmol)and imidazole (2.96 g, 44 mmol) were dissolved in 100 ml ethyl acetateand the solution was cooled to about 5° C. Chlorotriethylsilane (6.3 ml,38 mmol) was slowly added to the solution in 30 minutes at a temperaturemaintained at about 5-10° C. throughout the addition. The mixture wasbrought to room temperatures slowly. The precipitate was removed byfiltration. Subsequently, the reaction mixture was washed with 50 mlsaturated aqueous sodium bicarbonate solution twice, further washed withbrine (50 ml), dried over anhydrous magnesium sulfate, filtered, andconcentrated to obtain the crude product (13.2 g). The crude product waspurified by distillation to give the (R)-silyl ether as colorless oil(9.1 g, 91%).

¹H-NMR (CDCl₃/TMS): δ 7.18 (m, 1H), 6.93 (m, 2H), 6.80 (m, 1H), 4.71 (m,1H), 4.04 (m, 2H), 2.45 (d, 1H), 0.98 (t, 9H), 0.67 (q, 6H).

Example 2 5-Phenyl-(3S)-triethylsilyloxy-1-pentyne

The titled compound was obtained from 5-phenyl-(3S)-hydroxy-1-pentyne asan oil in 88% yield according to the same procedure as described inExample 1.

¹H-NMR (CDCl₃/TMS): δ 7.39 (m, 2H), 7.29 (m, 3H), 4.47 (m,1H), 2.89 (m,2H), 2.53 (d, 1H), 2.12 (m, 2H), 1.08 (t, 9H), 0.77 (q, 6H).

Example3 (3S)-Triethylsilyloxy-1-Octyne

The titled compound was obtained from (3S)-hydroxy-1-Octyne as an oil in95% yield according to the same procedure as described in Example 1.

Example4 (1E)-Tributylstannyl-(3S)-triethylsilyloxy-1-octene

To a stirred mixture of 20 g (78.6 mmol) of(3S)-triethylsilyloxy-1-octyne and 150 mg of azo-bis(isobutyronitrile)was added 30 ml (113 mmol) of tri-n-butyltin hydride using a syringeunder nitrogen atmosphere. The mixture was heated to about 130° C.,stirred for 2 h, and then cooled to room temperature. Excessivetri-n-butyltin hydride was removed by vacuum distillation at about 70°C. (0.05 mmHg). The product was then obtained at about 165° C. (0.05mmHg) under vacuum distillation as 36.5 g of a colorless liquid in ayield of 87%.

¹H NMR δ 4.05 (br m, 1H, C-3 H), 6.0 (m, 2H, olefin); ¹³C NMR δ 152.2,126.6, 77.0, 38.2, 32, 29.3,27.4, 25.1, 22.8, 14.1, 13.7, 9.6, 6.9, 5.1.

Example 5 5-Phenyl-(1E)-tributylstannyl-(3S)-triethylsilyloxy-1-pentene

The titled compound was obtained from5-phenyl-(3S)-triethylsilyloxy-1-pentyne as an oil in 82% yieldaccording to the same procedure as described in Example 4.

-   ¹H-NMR (CDCl₃/TMS): δ 7.33 (m, 2H), 7.23 (m,3H), 5.90˜6.21 (m, 2H),    4.15(q, 1H), 2.74 (m, 2H), 1.88 (m, 2H), 1.57 (m,2H), 1.30˜1.80 (m,    12H), 0.90˜1.08 (m, 24H), 0.67 (q, 6H).

Example6(1E)-Tributylstannyl-4-[3-(Trifluoromethyl)phenoxy]-(3R)-triethylsilyloxy-1-butene

The titled compound was obtained from4-[3-(trifluoromethyl)phenoxy]-(3R)-triethylsilyloxy-1-butyne as an oilin 74 % yield according to the same procedure as described in Example 4.

¹H-NMR (CDCl₃/TMS): δ 7.22 (m, 1H), 6.96 (m, 2H), 6.81 (m, 1H),5.90˜6.21 (m, 2H), 4.49 (m, 1H), 3.90 (d, 2H).

Example 7 (1 E)-Iodo-(3S)-triethylsilyloxy-1-octene

To a stirred solution of 5.3 g(1E)-tributylstannyl-(3S)-triethylsilyloxy-1-octene in 75 ml ether wasadded 2.5 g iodine. The solution was allowed to be stirred at roomtemperature for about 2 hours and concentrated to dry under vacuumevaporation. The crude product was further purified by columnchromatography on silica gel using a mixture of hexane and ether as agradient eluent. The yield of the titled compound was 2.2 g (63%).

¹H-NMR (CDCl₃/TMS): δ 6.49 (dd, 1H), 6.19 (d, 1H), 4.04 (q, 1H),1.20˜1.70 (m, 8H), 0.93 (t, 9H), 0.83 (t, 3H), 0.57 (q, 6H).

Example 8 Ethyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate

A 250-ml three-necked flask was flame dried and allowed to be cooled.Copper cyanide (2.7 g, 30 mmol) and 40 ml anhydrous tetrahydrofuran(THF) were added to the reaction flask, followed by dropwise addition of40 ml methyllithium (1.5M in ethyl ether) at about −10° C. Afterstirring the reaction mixture for 30 minutes, a solution of(1E)-tributylstannyl-(3S)-triethylsilyloxy-1-octene (15.9 g, 30 mmol) in20 ml anhydrous tetrahydrofuran was added. The reaction mixture wasallowed to be stirred at room temperature for 3 hours. Then, thereaction mixture was brought to −70° C. A solution of ethyl(3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate (6.3 g, 21 mmol) in20 ml anhydrous tetrahydrofuran was added to the reaction mixture. Thereaction was stirred at −70° C. for 30 minutes and quenched with 500 mlsaturated aqueous ammonium chloride containing 50 ml ammonium hydroxide.The reaction mixture was phase separated and the aqueous layer wasextracted with ethyl acetate. The organic layers were combined and driedover anhydrous magnesium sulfate. The solid was filtered off. Thesolvent was evaporated off under vacuum. The residue was furtherdissolved in 100 ml acetone and 20 ml water, followed by addition of 0.5g p-toluenesulfonic acid monohydrate. The reaction solution was stirredat room temperature for 1 hour and further subjected to vacuumevaporation until two separate layers were formed. 150 ml ethyl acetatewas added to the reaction and the reaction was allowed to be phaseseparated. The organic layer was washed with saturated sodiumbicarbonate solution and brine, dried over anhydrous magnesium sulfate,and evaporated to dryness. The crude product was purified bychromatography on silica gel using a mixture of hexane and ethyl acetateas a gradient eluent. Yield of the titled compound was 5.83 g (89%)containing a trace amount of 15-epimer. The 15-epimer can be removed bycrystallization of the titled compound from ether/hexane. 4.2 g titledcompound was obtained in a crystalline form (white to off-white powder).MP: 62° C.

¹H-NMR (CDCl₃/TMS): δ 5.69 (m,1H), 5.57 (m,1H), 4.15 (m, 4H), 3.38 (br,1H), 2.80 (dd, 1H), 2.15˜2.65 (m, 6H), 1.20˜1.84 (m, 10OH), 0.90 (t,3H); ¹³C-NMR (CDCl₃/TMS): δ 213.22, 172.31, 138.26, 131.06, 73.42,72.86, 61.55, 54.85, 51.64, 45.96, 37.95, 32.36, 32.35, 25.79, 23.24,14.81, 14.68.

Example 9 Benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate

A solution of (1E)-Iodo-(3S)-triethylsilyloxy-1-octene (35.4 g) in 200ml ether was cooled to −70° C. and 60 ml of 1.6M n-butyllithium solutionwas added. The solution thus obtained was labeled as Solution A andallowed to be stirred at −70° C. for 2 hours. To a dry flask was addedCuCN (8.3 g) and ether (50 ml). The solution was cooled to −20° C., towhich a 1.5M solution of methyllithium in ether (61 ml) was added. Thesolution mixture was labeled as Solution B and allowed to be stirred foranother 30 minutes. Subsequently, Solution B was cooled to −70° C. towhich previously prepared vinyllithium solution (Solution A) was added.The mixture was stirred for 1 hour while maintaining the temperature atabout −70° C. Benzyl (3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetate(26.2 g) in 50 ml of ether was added to the reaction mixture. Afterbeing stirred for another 20 minutes, the reaction mixture was pouredinto a mixture of 9/1 (v/v) saturated aqueous NH₄Cl/NH₄OH solution to bephase separated. The aqueous layer was extracted with ethyl acetate. Theorganic layers were combined and dried over anhydrous magnesium sulfate.The solid was filtered off, and the solvent was evaporated off undervacuum. The residue was dissolved in 300 ml acetone and 50 ml water,followed by addition of 2 g p-toluenesulfonic acid monohydrate. Thereaction solution was stirred at room temperatures for 1 hour andconcentrated until two separate layers were observed. 150 ml ethylacetate was added for extraction. The organic layer was further washedwith saturated sodium bicarbonate solution and brine, dried overanhydrous magnesium sulfate, and evaporated to dryness. The liquidresidue was purified by chromatography on silica gel using a mixture ofhexane and ethyl acetate as a gradient eluent. The titled compound wasobtained in a crystalline form. Yield: 74%. MP: 74° C.

¹H-NMR (CDCl₃/TMS): δ 7.39 (m,5H), 5.52˜5.71 (m,2H), 5.12 (dd, 2H),4.05˜4.20 (m,2H), 3.36(s, 1H), 2.79 (dd, 1H), 2.64 (m, 2H), 2.38˜2.55(m, 3H), 2.34 (dd,1H), 1.10˜1.80 (m,7H), 0.89 (t, 3H). ¹³C-NMR(CDCl₃/TMS): δ 213.05, 172.11, 138.37, 136.24, 130.24, 129.29, 129.08,128.70, 73.37, 72.62, 67.35, 54.81, 51.63, 45.93, 37.93, 32.35, 25.80,23.29, 14.60.

Example 10 2-Naphthyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 9 except thatthe equimolar substrate used in the reaction was 2-naphthyl(3R)-tetrahydropyranyloxy-5-oxo-1-cyclopenten-1-acetate instead ofbenzyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate. The titledcompound was prepared and obtained in a crystalline form. Yield: 63%.

¹H-NMR (CDCl₃/TMS): δ 7.87 (m, 3H), 7.58 (s, 1H), 7.50 (m, 2H), 7.25 (m,1H), 5.76 (m, 2H), 4.21(m, 2H), 2.87 (m, 3H), 2.61 (m, 2H), 2.42 (m,1H), 1.20˜1.80 (m, 8H), 0.87 (t, 3H).

Example 11 Benzyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate

A 100 ml flask equipped with a stirrer bar was charged with zirconocenechloride hydride (1.29 g, 5 mmol) and sealed with a septum. The flaskwas evacuated with a vacuum pump and purged with argon, which wasrepeated for 3 times. THF (15 ml) was subsequently added to the flaskand the mixture was stirred to generate a white slurry to which5-phenyl-(3S)-triethylsilyloxy-1-pentyne (1.37 g, 5 mmol) was added. Themixture was stirred for 30 minutes and cooled to −70° C. Upon additionof ethereal MeLi (3.5 ml, 5 mmol), a bright yellow solution was formed.Concurrently, lithium 2-thienylcyanocuprate (20 ml, 0.25M in THF) wasadded to the zirconium solution. The mixture was stirred for 15 minutesat −70° C. and benzyl(3R)-triethylsilyloxy-5-oxo-1-cyclopenten-l-acetate (0.90 g, 2.5 mmol)in ether (5 ml) was added. After 10 minutes, the mixture was quenchedwith 40 ml of 10% NH₄OH in saturated NH₄Cl aqueous solution. The productwas extracted with 50 ml of ether for 3 times and dried over MgSO₄. Thesolution was then filtered and the solvent was removed by vacuumevaporation. The liquid residue was dissolved in 20 ml acetone and 4 mlwater, followed by addition of 0.2 g p-toluenesulfonic acid monohydrate.The reaction solution was stirred at room temperature for 1 hour andconcentrated until two separate layers were observed. 30 ml ethylacetate was added for extraction and phase separation. The organic layerwas washed with saturated sodium bicarbonate solution and brine, driedover anhydrous magnesium sulfate, and subjected to vacuum evaporationfor removal of the solvent until dryness. The liquid residue was furtherpurified by chromatography on silica gel using a mixture of hexane andethyl acetate as a gradient eluent. The titled compound was obtained ina crystalline form. Yield: 82%. MP: 81° C.

¹H-NMR (CDCl₃/TMS): δ 7.17˜7.42 (m, 10H), 5.56˜5.78 (m, 2H), 5.1 (dd,2H), 4.13 (m, 2H), 2.16˜2.87 (m, 6H), 1.80˜2.10 (m, 2H);

¹³C-NMR(CDCl₃/TMS):δ 212.87, 172.07, 142.13, 138.15, 135.63, 129.28,129.17, 129.09, 129.06, 128.83, 126.70, 72.70, 72.39, 67.39, 54.71,51.62, 46.04, 39.52, 32.43, 32.42.

Example 12 (1′R,2′S,5′R)-Menthyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 8 except thatthe equimolar of the substrate used in the reaction was(1′R,2′S,5′R)-menthyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetateinstead of ethyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate. Thetitled compound can be prepared and obtained in a crystalline form.Yield: 62%. MP: 96° C.

¹H-NMR (CDCl₃/TMS): δ 5.59 (m, 2H), 4.59 (m, 1H), 4.05 (m, 2H), 2.71(m,1H), 2.49 (m,3H), 2.28 (m,2H).

Example 13 3-Ethoxycarbonylphenyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 8 except thatthe equimolar of the substrate used in the reaction was3-ethoxycarbonylphenyl(3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetate instead of ethyl(3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate. The titled compoundcan be prepared and obtained in Yield 68%. ¹H-NMR (CDCl₃/TMS): δ 7.94(d, 1H), 7.76 (s,1H), 7.47 (t, 1H), 7.31 (m, 1H), 5.75 (dd, 1H), 5.63(dd, 1H), 4.41 (q, 2H), 4.17 (m, 2H), 2.86 (m, 3H), 2.57 (m, 2H), 2.37(dd, 1H), 1.57 (m, 1H), 1.51 (m, 1H), 1.43 (t, 3H), 1.29 (m, 6H), 0.90(t, 3H).

Example 14 2-Cyanoethyl (1R,2R,3R)3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentane acetate

According to the same procedure as described in Example 8 except thatthe equimolar of the substrate used in the reaction was 2-cyanoethyl(3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetate instead of ethyl(3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate. The titled compoundcan be prepared and obtained in a crystalline form. Yield: 72%. MP: 54°C. ¹H-NMR (CDCl₃/TMS): δ 5.66 (m, 1H), 5.55 (m, 1H), 4.29 (m, 2H), 4.10(m, 2H), 2.79 (dd, 1H), 2.74 (t, 2H), 2.59 (m, 2H), 2.44 (m, 2H), 2.33(dd, 1H), 1.58 (m, 1H), 1.49 (m, 1H), 1.31 (m, 6H), 0.91 (t, 3H).

Example 15 Ethyl (1R,2R,3R)3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 8 except thatthe equimolar of the substrate used in the reaction was(1E)-tributylstannyl-5-phenyl-(3R)-triethylsilyloxy-1-pentene instead of(1E)-tributylstannyl-(3S)-triethylsilyloxy-1-octene. The titled compoundcan be prepared and obtained in 68% yield. ¹H-NMR (CDCl₃/TMS): δ 7.30(m, 2H), 7.22 (m, 3H), 5.71 (dd, 1H), 5.58 (dd, 1H), 4.11 (m, 4H), 3.34(brs, 2H), 2.30˜2.90 (m, 6H), 1.70˜1.95 (m, 2H), 1.25 (t, 3H).

Example 16 4-Morpholineethyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 8 except thatthe equimolar of the substrate used in the reaction was4-morpholineethyl (3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetateinstead of ethyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate, thetitled compound can be prepared and obtained in 70% yield. ¹H-NMR(CDCl₃/TMS): δ 5.64 (dd, 1H), 5.54 (dd, 1H), 4.21 (m, 4H), 4.08 (m, 2H),3.72 (t, 4H), 2.77 (dd, 1H), 2.63 (t, 2H), 2.57 (t, 1H), 2.52 (brs, 4H),2.37 (m, 2H), 1.56 (m, 1H), 1.47 (m, 1H), 1.30 (m, 6H), 0.90 (t, 3H).

Example 17 2-Naphthyl (1R,2R,3R)3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 15 except thatequimolar of the substrate used in the reaction was 2-naphthyl(3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetate instead of ethyl(3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate. The titled compoundcan be prepared and obtained in a crystalline form. Yield: 72%. MP: 123°C.

Example 18 (1′R,2′S,5′R)-Menthyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate

According to the same procedure as described in Example 15 except thatthe equimolar of the substrate used in the reaction was(1′R,2′S,5′R)-menthyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetateinstead of ethyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate. Thetitled compound can be prepared and obtained in a crystalline form.Yield: 67%. MP: 115° C.

Example 19˜20 Ethyl (1R,2R,3R)3-hydroxy-2-[5-phenyl-(3R)-hydroxy-pentanyl]-5-oxo-cyclopentane acetate

Example 19 1.25 g of

(3S)-3-(tert-butyldimethylsilyloxy)-5-bromo-1-phenylpentane wasdissolved in ether (20 ml) and cooled to −70° C. T-BuLi (1.7M inpentane, 4.3 ml) was added dropwise and the mixture was stirred for 30minutes. (2-Thienyl)Cu(CN)Li (0.25M, 30 ml) was added dropwise thereto.The reaction solution was stirred for 1 hour and ethyl(3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetate (0.74 g, 2.5 mmol)in ether (5 ml) was added. After 10 minutes, the mixture was quenchedwith 40 ml of 10% NH₄OH in saturated NH₄Cl aqueous solution. The productwas extracted with 50 ml of ether for 3 times and dried over MgSO₄. Thesolution was then filtered and the solvent was removed by vacuumevaporation. The liquid residue was dissolved in dichloromethane (20 ml)and added with hydrofluoride solution in pyridine (2.5 ml) at 0° C., andstirred for 3 hours. Upon completion of the reaction, the reactionmixture was poured into a saturated sodium bicarbonate aqueous solutionand the aqueous phase was further extracted with ethyl acetate twice.The organic layers were combined, dried over MgSO₄, filtered, andconcentrated. The residue was purified by column chromatography to givethe titled compound in a Yield of 48%.

Example 20 To a stirred solution of ethyl (1R,2R,3R)

3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate (1 g) in ethyl acetate (10 ml) was added 5% Pd—C catalyst (0.2g). The solution was stirred for 30 hours under hydrogen environment.The solution was filtered to obtain a filtrate which is furtherconcentrated to dryness. The crude product was subjected to furtherpurification by flash column chromatography (over silica gel witheluting solvents being ethylacetate:hexane=1:1) to obtain the titledcompound as a colorless oil (0.68 g)

¹H-NMR (CDCl₃/TMS): δ 7.31 (m, 2H), 7.22 (m, 3H), 4.15 (q, 2H), 3.65˜4.3(m,2H).

Example21 Ethyl (1R,2R,3R)3-triethylsilyloxy-2-[(3S)-triethylsilyloxy-1-octenyl]-5-oxo-cyclopentaneacetate

Ethyl 3-hydroxy-2-(3-hydroxy-1-octenyl)-5-oxo-cyclopentaneacetate (12.5g, 40 mmol) was dissolved in 100 ml ethyl acetate, added with 6.8 gimidazole, and stirred until the reaction system became homogeneous.14.7 ml of triethylsilyl chloride was added slowly into the reactionmixture. The stirred reaction mixture was brought to room temperatureand stirred overnight. The reaction mixture was filtered to obtain afiltrate. Subsequently, the reaction mixture was washed with 30 mlsaturated sodium bicarbonate aqueous solution twice, further washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to obtain the crude product (20.2 g).

Example 22˜31 (3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-3-hydroxy-1-octenyl]-2H-cyclopenta[β] furan-2-one

¹H-NMR (CDCl₃/TMS): δ 5.62 (m, 1H), 5.48 (m, 1H), 4.31 (m, 1H),3.96˜4.17 (m, 2H), 0.89 (t, 3H).

Example 22 Benzyl

(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-Cyclopentaneacetate (20 g, 49 mmol) in 200 ml THF was cooled by dry ice methanolbath to about −70° C. Then 1.0M lithium tri-(sec-butyl)-borohydride (49ml) was added dropwise into the solution. The reaction was stirred for 2hours and quenched by 100 ml saturated ammonium chloride aqueoussolution. After phase separation, the aqueous layer was extracted twicewith ethyl acetate. The organic layers were combined, washed with brine,dried over anhydrous magnesium sulfate, and evaporated under reducedpressure. The concentrate was purified by column chromatography onsilica gel. The titled compound was obtained in 82% yield.

Example 23: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction wasethyl (1R,2R,3R)3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate insteadof benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in 75% Yield.

Example 24: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction was2-naphyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetateinstead of benzyl(1R,2R,3R)3-hydroxy-2-[(3S)-hydroxy-l-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in 63% Yield.

Example 25: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction wasmenthyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetateinstead of benzyl (1R,2R,3R)3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate. Thetitled compound can be prepared and obtained in 69% Yield.

Example 26: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction was4-morpholineethyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetateinstead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-Cyclopentaneacetate. The titled compound can be prepared and obtained in 67% Yield.

Example 27: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction was3-ethoxycarbonylphenyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-l-octenyl]-5-oxo-cyclopentaneacetateinstead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-l-octenyl]-5-oxo-cyclopentaneacetate,the titled compound can be prepared and obtained in 69% Yield.

Example 28: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction was2-cyanoethyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetateinstead of Benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate. The titled compound can be prepared and obtained in 76% Yield.

Example 29: According to the same procedure as described in Example 22except that the equimolar of the reducing agent used in the reaction wassodium tri-sec-butylborohydride instead of lithiumtri-sec-butylborohydride. The titled compound can be prepared andobtained in 69% Yield.

Example 30: According to the same procedure as described in Example 22except that the equimolar of the reducing agent used in the reaction wasdiisobutylaluminum hydride instead of lithium tri-sec-butylborohydride.The titled compound can be prepared and obtained in 42% Yield.

Example 31: According to the same procedure as described in Example 22except that the equimolar of the reducing agent used in the reaction waslithium tri-tert-butoxyaluminum hydride instead of lithiumtri-sec-butylborohydride. The titled compound can be prepared andobtained in 57% Yield.

Example32 (3aR, 4R, 5R, 6aS)-hexahydro-5-triethylsilyloxy-4-[(1E,3S)-3-triethylsilyloxy-1-octenyl]-2H-cyclopenta [β] furan-2-one

According to the same procedure as described in Example 22 except thatthe equimolar of the substrate used in the reaction was ethyl(1R,2R,3R)-3-triethylsilyoxy-2-[(3S)-triethylsilyloxy-1-octenyl]-5-oxo-cyclopentaneacetateinstead of ethyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The title compound can be prepared and obtained in 95% Yield.

Example 33˜36 (3aR, 4R, 5R, 6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-5-phenyl-3-hydroxy-1-pentenyl]-2H-cyclopenta [β] furan-2-one

Example 33: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction wasethyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate instead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in 75% Yield.

Example 34: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction was2-naphathyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate instead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in 68% Yield.

Example 35: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction was(1′R, 2′S,5′R)-menthyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate instead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in 77% Yield.

Example 36: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction wasbenzyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3S)-hydroxy-1-pentenyl]-5-oxo-cyclopentaneacetate instead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in 78% Yield.

¹H-NMR (CDCl₃/TMS): δ 7.04˜7.28 (m, 5H), 5.57 (m, 1H), 5.39 (m, 1H),4.81 (m, 1H), 4.03 (m, 1H), 3.87 (m,1H), 1.58˜2.85 (m,10H); ¹³C-NMR(CDCl₃/TMS):

δ 177.47, 142.21, 137.13, 130.85, 129.16, 129.10, 125.88, 83.10, 77.95,72.60, 55.88, 43.17, 40.52, 35.38, 34.83, 32.41.

Example 37˜40 (3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[5-phenyl-(3R)-hydroxy-pentanyl]-2H-cyclopenta[β] furan-2-one

¹H-NMR (CDCl₃/TMS): δ 0.85˜1.95 (m, 9H), 2.30 (m, 2H), 2.50 (m, 1H),2.68 (m, 1H), 2.80 (m, 2H), 3.63 (m, 1H), 4.03 (m, 1H), 4.94 (m, 1H),7.15˜7.42 (m, 5H)

Example 37: According to the same procedure as described in Example 22except that the equimolar of the substrate used in the reaction is ethyl(1R,2R,3R)-3-hydroxy-2-[5-phenyl-(3R)-hydroxy-pentanyl]-5-oxo-cyclopentaneacetate instead of benzyl(1R,2R,3R)-3-hydroxy-2-[(3S)-hydroxy-1-octenyl]-5-oxo-cyclopentaneacetate.The titled compound can be prepared and obtained in a crystalline form(yield: 75%).

Example 38: To a solution of(3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-5-phenyl-3-hydroxy-1-pentenyl]-2H-cyclopenta[β] furan-2-one (10 g) in ethyl acetate (100 ml) was added 10% Pt—Ccatalyst (1 g) and sodium hydroxide (0.2 g). The solution was stirredunder hydrogen atmosphere for 18 hours. After filtration, the filtratewas concentrated in vacuum to remove the solvent. The crude product wassubjected to purification using flash column chromatography (over silicagel with developing solvent being ethyl acetate:hexane=1:1). The titledcompound was obtained in a crystalline form (yield 72%).

Example 39: To a solution of (3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-5-phenyl-3-hydroxy-1-pentenyl]-2H-cyclopenta[β] furan-2-one (1 g) in ethyl acetate (10 ml) was added 5% Pd—Ccatalyst (0.2 g) and sodium hydroxide (0.05 g). The solution was stirredunder hydrogen atmosphere overnight. After filtration, the filtrate wasconcentrated by vacuum evaporation. The crude product was subjected toflash column chromatography (on silica gel, eluted with ethylacetate:hexane=1:1). The titled compound was obtained in a crystallineform (yield 78%).

Example 40: To a solution of (3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-5-phenyl-3-hydroxy-1-pentenyl]-2H-cyclopenta[β] furan-2-one (1 g) in ethyl alcohol (10 ml) was added with Raneynickel catalyst (0.5 g) and sodium hydroxide (0.1 g). The solution wasstirred under hydrogen atmosphere for 10 hours. After filtration, thefiltrate was concentrated by vacuum evaporation. The crude product wassubjected to flash column chromatography (on silica gel eluted withethyl acetate:hexane=1:1). The titled compound was obtained in acrystalline form (yield 68%). MP: 68˜72° C.; ¹H-NMR (CDCl₃/TMS): δ7.15˜7.42 (m, 5H), 4.94 (m, 1H), 4.03 (m, 1H), 3.63 (m, 1H), 2.80 (m,2H), 2.68 (m, 1H), 2.50 (m, 1H), 2.30 (m, 2H), 0.85˜1.95 (m, 9H);¹³C-NMR(CDCl₃/TMS): δ 178.04, 142.41, 129.19, 129.07, 126.68, 84.45,78.32, 72.03, 54.72, 43.95, 41.35, 39.79, 36.65, 35.89, 32.73, 29.67.

Example 41 (3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[(3R)-hydroxy-4-(3-trifluoromethyl)phenoxy-1-butenyl]-2H-cyclopenta[β] furan-2-one

Ethyl(1R,2R,3R)-3-hydroxy-2-[(3R)-hydroxy-4-(3-trifluoromethyl)phenoxy-1-butenyl]-5-oxo-cyclopenaneacetate was prepared according to a similar procedure as described inExample 11 except that the equimolar of the substrates used in thereaction were ethyl (3R)-triethylsilyloxy-5-oxo-1-cyclopenten-1-acetateand 4-[3-(trifluoromethyl)phenoxy]-(3R)-triethylsilyloxy-1-butyneinstead of benzyl (3R)-triethylsilyoxy-5-oxo-1-cyclopenten-1-acetate and5-phenyl-(3S)-triethylsilyloxy-1-pentyne. The crude product thusobtained was subjected to reduction/lactonization directly according tothe same procedure as described in Example 22. The titled compound canbe prepared and obtained in a yield of 25%.

¹H-NMR (CDCl₃/TMS): δ 7.41 (m, 1H), 7.25 (m, 1H), 7.14 (s, 1H), 7.09 (m,1H), 5.75 (m, 2H), 4.93 (q, 1H), 4.57 (s, 1H), 4.04 (m, 2H), 3.92(m,1H), 2.28˜2.82 (m, 4H), 1.92˜2.18 (m, 2H).

Example 42 (3aR, 4R, 5R,6aS)-hexahydro-5-tert-butyldimethylsilyloxy-4-[(1E,3s)-3-tert-butyldimethylsilyloxy-1-octenyl]-2H-cyclopenta [β]furan-2-one

(3aR, 4R, 5R, 6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-3-hydroxy-1-octenyl]-2H-cyclopenta [β] furan-2-one (10.7 g, 40 mmol)was dissolved in 100 ml ethyl acetate, added with 8.2 g imidazole, andstirred until the reaction system became homogeneous. 15.7 gtert-butyldimethylsilyl chloride dissolved in 50 ml ethyl acetate wasgradually added to the reaction mixture. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was filteredto obtain a filtrate. Subsequently, the reaction mixture was washed with50 ml saturated aqueous sodium bicarbonate solution twice, furtherwashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to obtain the crude product. The crude product wascrystallized from hexane at −70° C. (cold dry ice bath temperatures),filtered, and washed with cold hexane. The solid was dried to give thetitled compound as a white solid. MP: 74° C. (14.3g). ¹H-NMR(CDCl₃/TMS): δ 5.47 (dd, 1H), 5.35 (dd, 1H), 4.93 (td, 1H), 4.02 (q,1H), 3.96 (q,1H), 2.73 (m, 1H), 2.62 (m, 1H), 2.45 (m, 2H), 2.22 (m,1H), 1.95 (m, 1H), 1.44 (m, 1H), 1.38 (m, 1H), 1.27 (m, 6H), 0.82˜0.88(m,3H), 0.86 (s, 9H), 0.85 (s, 9H), 0.02 (m,12H).

Example 43(3aR,4R,5R,6aS)-Hexahydro-5-triethylsilyoxy-4-[5-phenyl-(3R)-triethylsilyloxy-pentanyl]-2H-cyclopenta[β] furan-2-one

(3aR, 4R, 5R,6aS)-hexahydro-5-hydroxy-4-[5-phenyl-(3R)-triethylsilyloxy-pentanyl]-2H-cyclopenta[β] furan-2-one (12.2 g, 40 mmol) was dissolved in 120 ml ethyl acetate,added with 8.2 g imidazole, and stirred until the reaction system becamehomogeneous. 15.7 g triethylsilyl chloride was added to the reactionmixture and the reaction mixture was stirred at room temperature for 30minutes. The reaction mixture was filtered to obtain a filtrate, whichwas then washed twice with 50 ml saturated aqueous sodium bicarbonatesolution, and washed with 50 ml brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated to obtain the crude product (21 g).

Example 44 Preparation of Latanoprost

To a stirred solution of (3aR, 4R, 5R,6aS)-hexahydro-5-triethylsilyoxy-4-[5-phenyl-(3R)-triethylsilyloxy-pentanyl]-2H-cyclopenta[β] furan-2-one (21 g, 39.4 mol) in dry toluene (250 ml) at −78° C. wasadded a solution of diisobutylaluminum hydride (60 ml, 20% in hexane)dropwise. After being stirred for 2 hours, the reaction mixture waspoured into a solution of 2M sodium hydrogensulfate and stirred for 30minutes. The aqueous phase was extracted twice with toluene (2×100 ml).The combined organic layers was washed with brine, dried over anhydrousmagnesium sulfate, and evaporated to dryness. The crude correspondinglactol was obtained as a colorless oil. Potassium tert-butoxide (27 g,240 mmol) was added to a suspension of4-carboxybutyl-triphenylphosphonium bromide (53 g, 120 mmol) in 500 mlTHF. The mixture was cooled to less than −10° C. and the crude lactolobtained above was added. The mixture was stirred for 18 hours and 200ml saturated aqueous ammonium chloride solution was added. Upon phaseseparation, the organic as well as the aqueous layers were separatelycollected. The pH of the aqueous phase was adjusted to 6 with 2M sodiumhydrogen sulfate solution and then the aqueous layer was extracted with500 ml ethyl acetate twice. The combined organic layers were dried overanhydrous magnesium sulfate, filtered, and evaporated under vacuum. Theliquid residue was further dissolved in 120 ml DMF and added with 15 g2-iodopropane, followed by addition of 10 g K₂CO₃. The reaction solutionwas stirred at room temperature for 12 hours, then diluted with 500 mlethyl acetate, and washed with water (2×100 ml). The organic layer wasdried over anhydrous magnesium sulfate, filtered, concentrated, andpurified by column chromatography to obtain the protected Latanoprost.The protected Latanoprost was dissolved in 100 ml of THF and 10 ml ofwater, added with 1 ml of conc. HCl, stirred at room temperatures for 30minutes. 50 ml saturated aqueous sodium bicarbonate solution was thenadded. The aqueous layer was extracted twice with ethyl acetate (100ml). The combined organic layers were washed with brine, dried overanhydrous magnesium sulfate, and evaporated to dryness. The crudeproduct was subjected to flash column chromatography (over silica geleluted with ethylacetate:hexane=1:1). The titled compound was obtainedas a colorless oil (5.4 g). The product was further analyzed by HPLC andabout 2˜3% 5-trans Latanoprost without 15-β isomer was found in thefinal product.

Example 45

Preparation of Dinoprost

To a stirred solution of (3aR, 4R, 5R,6aS)-hexahydro-5-triethylsilyloxy-4-[(1E,3S)-3-triethylsilyloxy-1-octenyl]-2H-cyclopenta [β] furan-2-one (19.9 g,40 mol) in dry toluene (250 ml) at −78° C. was added a solution ofdiisobutylaluminum hydride (60 ml, 20% in hexanes) dropwise. After beingstirred for 2 hours, the reaction mixture was poured into a 2M aqueoussolution of sodium hydrogensulfate and stirred for 30 minutes. Theaqueous layer was collected separately from the organic layer andextracted twice with toluene (100 ml). The combined organic layers waswashed with brine, dried over anhydrous magnesium sulfate, andevaporated to dryness. The crude Lactol was obtained as a colorless oil.Potassium tert-butoxide (27 g, 240 mmol) was added to a suspension of4-carboxybutyl-triphenylphosphonium bromide (53 g, 120 mmol) in 500 mlTHF. The mixture was cooled to less than −10° C. and the crude Lactolwas added. The mixture was further stirred at less than −10° C. for 18hours and then added with 200 ml saturated ammonium chloride solution.Upon phase separation, the aqueous layer and the organic layer wereseparately collected. The pH of the aqueous layer was adjusted to 4 with2M sodium hydrogen sulfate solution and extracted twice with 500 mlethyl acetate. The combined the organic layers was dried over anhydrousmagnesium sulfate, filtered, and evaporated under vacuum. A slightlyyellowish oil was thus obtained. To a stirred solution of the aboveobtained yellowish oil, 100 ml of THF, 10 ml of water, and 1 ml of conc.HCl were added. After being stirred at room temperature for 30 minutes,the reaction mixture was added with 50 ml saturated sodium bicarbonatesolution. The aqueous layer was separately collected and extracted twicewith ethyl acetate (100 ml). The combined organic layers was washed withbrine, dried over anhydrous magnesium sulfate, and evaporated todryness. Crude Prostagladin F2α (Dinoprost) thus obtained was analyzedby HPLC and about 2˜3% 5-trans PGF2α a without 15-β isomer was found inthe final product.

1. A process for preparing a Lactone of Formula I having an enantiomericpurity higher than 95% enantiomeric excess:

wherein R₂ is a single bond or a C₁₋₄-alkylene or —CH₂O—; R₃ is aC₁₋₇-alkyl or an aryl or an aralkyl, each of which is unsubstituted orsubstituted by a C₁₋₄-alkyl, a halogen and a trihalomethyl;

is a single bond or a double bond; and X₁ and X₂ are independentlyhydrogen or are P₁ and P₂, respectively, where P₁ and P₂ are the same ordifferent protecting groups for the hydroxyl groups, comprising thesteps of: (a) reacting a compound of Formula IV having an optical purityhigher than 90% enantiomeric excess:

wherein Z is an arbitrary group that does not participate in a couplingand deprotection reactions but acts as a leaving group in areduction/lactonization reaction; P₁ is a protecting group for thehydroxyl group, with a cuprate derived from a compound of Formula V-1,Formula V-2 or Formula V-3, each of which has an optical purity higherthan 90% enantiomeric excess:

wherein Y is a halogen; R₆ is a lower alkyl; P₂ is a protecting groupfor the hydroxyl group;

, R₂ and R₃ are as defined above; to form a compound of Formula II-1

(b) optionally removing the protecting group P₁ or P₂, or both P₁ and P₂to form a compound of Formula II

(c) optionally hydrogenating the compound of Formula II under hydrogen,with a catalyst containing a metal selected from the group of palladium,platinum, rhodium and nickel and a mixture thereof, and (d)reducing/lactonizing the compound of Formula II, with an effectiveamount of a reducing agent of the Formula M₁M₂(R₅)_(n)H, wherein M₁ islithium, potassium, or sodium, or absent; M₂ is aluminum or boron; R₅ ishydrogen, an alkyl or an alkoxyl; and n is 2 or 3, to form a compound ofFormula I.
 2. A process according to claim 1, wherein X₁ and X₂ arehydrogen, both P₁ and P₂ are removed in step (b), and step (c) isabsent.
 3. The process of claim 2, further comprising isolating thecompound of Formula II or I by crystallization.
 4. The process accordingto claim 1, wherein Z is —OR₁ and R₁ at each occurrence is independentlyan alkyl, an alkenyl, an alkynyl, an aryl, or an aralkyl, each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy,thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl,arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl or aheterocyclic group selected from the group consisting of pyridinyl,thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl,piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl.
 5. Theprocess according to claim 1, wherein the reducing agent is selectedfrom lithium tri-sec-butylborohydride, lithium trisamylborohydride,sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, orpotassium trisamylborohydride or a mixture thereof.
 6. The processaccording to claim 1, wherein the reducing agent is lithiumtri-sec-butylborohydride.